This application is a 371 of PCT JP/98/04456 Oct. 2, 1998
This invention relates to novel biphenyl-5-alkanoic acid derivatives or salt thereof and a pharmaceutical composition containing the same as an active ingredient, especially IgE antibody production suppressor and drugs for treatment and prevention of allergic diseases characterized by IgE antibody suppressive action.
Allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis and anaphylaxis are classified into type I allergic reaction. The type I allergic reaction consists of, generally, the following three steps during the process of generation. Namely, these are: (1) the first step: antigen is entered into the body, and immunoglobulin E (IgE) is produced as a result of interaction with antigen-presenting cells such as macrophage, T cells and B cells, then the IgE antibody is bound with receptor on the cell membrane of mast cells and basophils to establish sensitization; (2) the second step: the reentry of antigen results to bind with IgE which is bound with the receptor, to generate degranulation of mast cells or basophils by antigen-antibody reaction to release chemical mediators such as histamine and SRS-A; and (3) the third step: the released chemical mediators induce contraction of the smooth muscle, capillary hyperpermeability and increase in mucous secretion to lead allergic reaction.
As above explained, the type I allergic reaction has known to be induced by IgE antibody production, and, in fact, serum or tissue levels of IgE antibody in patients with the aforementioned allergic diseases showed, in most cases, higher than those of the healthy subjects. Consequently, a compound, which selectively suppresses IgE antibody production, might be a useful agent for causal therapy of allergic diseases, and development of such a compound and its pharmaceutical product has been desired.
The known example of compound, which has similar structure of the compound of the present invention, is, for example, 3-(2-methoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid (J. Am. Chem. Soc., 75:2334, 1953) as choleretic agent. The said compound has different structure from the compound of the present invention in the ether moiety in phenolic hydroxy group in its structure, and in addition, no information on an action of IgE antibody production is disclosed. The same report discloses 3-(3-phenyl-4-methoxybenzoyl)propionic acid, however the said compound is different from the compound of the present invention in the ether moiety, furthermore a part of an oxo group in methylene moiety between biphenyl moiety and carboxy group is different in each other.
In the reference, Chem. Pharm. Bull. 35(5):1755, 1987, discloses methyl 3-(4xe2x80x2-allyloxy-2-benzyloxy-1,1xe2x80x2-biphenyl-5-yl)propionate is disclosed, however it is different from ether moiety from the compound of the present invention. In addition, the said compound was synthesized as an intermediate of a natural compound magaldehyde and no pharmacological action was disclosed. Further, in the said reference, on page 1762, methyl 3-(2,4xe2x80x2-dihydroxy-1,1xe2x80x2-biphenyl-5-yl)propionate and methyl 3-(4xe2x80x2-allyloxy-2-hydroxy-1,1xe2x80x2-biphenyl-5-yl)propionate were reported, however it was different in its ether moiety from the compound of the present invention, furthermore no pharmacological action has reported.
DE-4019307 and Japanese Patent Unexamined Publication No. Hei 4-230252 disclose methyl 2-methoxyimino-3-(4xe2x80x2-chloro-2-methoxy-1,1xe2x80x2-biphenyl-5-yl)propionate as harmful organisms preventive agent. The said compound is different from the compound of the present invention in the structure on the points having different structure in the ether moiety and having methoxyimino group in methylene moiety between biphenyl moiety and carboxy group. In addition, no action about IgE antibody production is disclosed.
DE-2513157 and Japanese Patent Unexamined Publication No. Sho 50-135050 disclose methyl 4-oxo-4-(2-methoxy-1,1xe2x80x2-biphenyl-5-yl)-2-methylene butyric acid as anti-inflammatory agent. The said compound is different from the compound of the present invention on the point that it has ether moiety and has oxo group and methylene group in the methylene moiety between biphenyl moiety and carboxy group. In addition, no IgE production is disclosed.
In Japanese Patent Unexamined Publication No. Sho 58-55469 describes 3-(3-t-butoxy-2-hydroxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid as a stabilizer for resin. The said compound is different from the compound of the present invention on the point of substituents in the ether moiety and biphenyl moiety. Further, no pharmacological action is disclosed.
J. Med. Chem. 11:1139, 1968, discloses 4-(4-butoxy-1,1xe2x80x2-biphenyl-5-yl)-3-hydroxy butyric acid as anti-inflammatory agent. The said compound is different from the compound of the present invention on the point of position of substituent in ether moiety and having hydroxy group in methylene moiety between biphenyl moiety and carboxy group. Further, no IgE antibody production is disclosed.
In Japanese Patent Unexamined Publications No. Hei 4-95025 and No. Hei 4-95049 disclose biphenyl-5,5xe2x80x2-bis-alkanoic acid derivative as an aldose reductase inhibitor. The said compound is different from the compound of the present invention on the point having alkanoic acid in both of benzene rings in biphenyl moiety. Further, no IgE antibody production is disclosed.
U.S. Pat. No. 5,391,817 and Japanese Patent Unexamined Publication No. Hei 7-223997 disclose biphenyl derivatives as biaryl phospholipase A2 inhibitor. The said compounds are different from the compound of the present invention on the point of ether moiety and no compound of the present invention is included in their claims. Further, no IgE antibody production is disclosed in these patents.
Problems to be Solved by the Invention
An aspect of the present invention is to provide a compound for treatment and prevention of allergic diseases caused by type I allergic reaction, which is suppressed by selectively suppressing IgE antibody production.
Means for Solving the Problems
In order to solve the above problems, we have extensively studied and found that the novel compound biphenyl-5-alkanoic acid derivatives represented by the general formula shown below have selective and superior suppressive action against IgE antibody production, then completed the present invention.
An object of the present invention is to provide a compound of the general formula (I) or salt thereof. 
wherein n is an integer of either 2 or 3, R is straight or branched saturated alkyl of carbon numbers 4 or 5 (a), cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or xe2x80x94(CH2)mW, proviso that saturated alkyl (a) may optionally be substituted by hydroxy, oxo or halogen, m is an integer of 1-3, W is carboxy or xe2x80x94CONR1R2, in which R1 and R2 are in together or each separately hydrogen or lower alkyl of C1-4, Y is hydroxy or amino, A is hydrogen, hydroxy, methoxy, nitro or xe2x80x94NHZ, in which Z is xe2x80x94CO R3 or xe2x80x94SO2 R4, in which R3 is hydrogen, saturated alkyl (b) of C1-4 or xe2x80x94NR52, the saturated alkyl (b) may optionally be substituted by hydroxy or halogen, R4 is saturated alkyl (c) of C1-4 or xe2x80x94NR62, the saturated alkyl (c) may optionally be substituted by halogen, R5 and R6 are hydrogen or lower alkyl of C1-4, and Q is hydrogen, hydroxy or methoxy [hereinafter sometimes designates as xe2x80x9cthe compound (I)xe2x80x9d].
Another object of the present invention is to provide a drug comprising the compound of the above general formula (I) or pharmacologically acceptable salt thereof as an active ingredient.
In the above general formula (I), n is defined as any one of integer of 2 or 3. No effect is obtained wherein n is 1 or 4. Since it is extremely characteristics when n is 2 or 3, ethylene in 2 or trimethylene in 3 is preferable.
A group R is defined as straight or branched saturated alkyl of carbon numbers 4 or 5 (a), cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or xe2x80x94(CH2)mW, proviso that saturated alkyl (a) may optionally be substituted by hydroxy, oxo or halogen, and m is an integer of 1-3, and W is carboxy or xe2x80x94CONR1R2, in which R1 and R2 are in together or each separately hydrogen or lower alkyl of C1-4.
In a group R, examples of straight or branched saturated alkyl of carbon numbers 4 or 5 are n-butyl, isobutyl, 1-methylpropyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl and 1-methylbutyl. Among them, n-butyl, isobutyl, n-pentyl, and isopentyl are preferable, and n-butyl is most preferable.
In a group R, examples of straight or branched saturated alkyl of carbon numbers 4 or 5 substituted by hydroxy are straight or branched saturated alkyl of carbon numbers 4 or 5 substituted by a hydroxy in any carbons except for carbon constituting ether bonding in the saturated alkyl. Examples are 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl and 5-hydroxypentyl. Among them, 2-hydroxybutyl and 3-hydroxybutyl are preferable.
In a group R, examples of straight or branched saturated alkyl of carbon numbers 4 or 5 substituted by oxo are straight or branched saturated alkyl of carbon numbers 4 or 5 substituted by an oxo in a secondary carbon except for carbon constituting ether bonding in the saturated alkyl. Examples are 2-oxobutyl and 2-oxopentyl, and 2-oxobutyl is a preferable example.
A xe2x80x9chalogenxe2x80x9d in a group R of straight or branched saturated alkyl of carbon numbers 4 or 5 substituted by halogen means fluorine, chlorine, bromine or iodine. Examples of straight or branched saturated alkyl of carbon numbers 4 or 5 substituted by halogen are straight or branched saturated alkyl of carbon numbers 4 or 5 substituted by 1-3 halogens in any carbons except for carbon constituting ether bonding in the saturated alkyl. Examples are 2-chlorobutyl, 3-chlorobutyl, 2-chloropentyl, 3-chloropentyl, 4-chloropentyl, 5-chloropentyl, 4-bromobutyl and 4,4,4-trifluorobutyl. 3-chlorobutyl and 4,4,4-trifluorobutyl are preferable.
In a group R, cyclopentyl, cyclohexyl, cyclopentylmethyl and cyclohexylmethyl are preferable, and cyclohexylmethyl is most preferable.
In a group R, wherein R is xe2x80x94(CH2)mW, m is preferably integers of 1-3, especially methylene, in which m is 1, is preferable. W is most preferably a carboxy. When W is xe2x80x94CONR1R2, examples of R1 and R2 are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, and R1 and R2 can be the same or different. Among them, hydrogen, methyl and ethyl are preferable, and hydrogen is most preferable. Consequently, when W is xe2x80x94CONR1R2, preferable examples are carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl, and among them, carbamoyl is most preferable.
Examples of xe2x80x94(CH2)mW are carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl, (N-methylcarbamoyl)methyl, (N-ethylcarbamoyl)methyl, (N,N-dimethylcarbamoyl)methyl, (N,N-diethylcarbamoyl)methyl, 2-(N,N-dimethylcarbamoyl)ethyl and 3-(N,N-dimethylcarbamoyl)propyl. Among them, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, carbamoylmethyl, and (N,N-dimethylcarbamoyl)methyl are preferable, especially carboxymethyl and carbamoylmethyl are most preferable.
When R contains asymmetric carbon, in case of one asymmetric carbon, two optical isomers, and in case of two asymmetric carbons, four optical isomers can be possible. Any these isomers are preferable examples. In a mixture thereof, it is preferable for easier production.
A group Y is defined as hydroxy or amino, and any substituents are preferable.
A group A is hydrogen, hydroxy, methoxy, nitro or xe2x80x94NHZ, in which Z is xe2x80x94COR3 or xe2x80x94SO2 R4, in which R3 is hydrogen, saturated alkyl (b) of C1-4 or xe2x80x94NR52. The saturated alkyl (b) may optionally be substituted by hydroxy or halogen. R5 is hydrogen or lower alkyl of C1-4. R4 is saturated alkyl (c) of C1-4 or xe2x80x94NR62. The saturated alkyl (c) may optionally be substituted by halogen. R6 is hydrogen or lower alkyl of C4. Any substituents are preferable for the group A, and especially hydrogen is most preferable substituent.
When the group A is xe2x80x94NHZ and Z is xe2x80x94COR3, a group R3 is, for example, preferably hydrogen. When the group R3 is saturated alkyl (b) of C14, the saturated alkyl (b) may optionally have branched chain, and examples thereof are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Among them, methyl and ethyl are preferable, and methyl is most preferable. In the saturated alkyl (b), any carbons in the saturated alkyl may optionally be substituted by one hydrogen. Examples thereof are hydroxymethyl and 2-hydroxyethyl, and hydroxymethyl is preferable. In the saturated alkyl (b), any carbons in the saturated alkyl may optionally be substituted by 1-3 halogens. Examples thereof are chloromethyl and trifluoromethyl, and chloromethyl is preferable. When R3 is xe2x80x94NR52, the group R5 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Among them, hydrogen and methyl are preferable, and hydrogen is most preferable.
Examples of xe2x80x94NR52 are amino, dimethylamino and diethylamino. Among them, amino and dimethylamino are preferable, and amino is most preferable. Consequently, preferable examples of xe2x80x94COR3 are formyl, acetyl, propionyl, hydroxyacetyl, chloroacetyl, carbamoyl and N,N-dimethylcarbamoyl. Among them, formyl, acetyl and carbamoyl are most preferable examples.
When a group A is xe2x80x94NHZ and the group Z is xe2x80x94SO2R4, in which R4 is saturated alkyl (c) of C1-4, the saturated alkyl (c) may optionally have branched chain. Examples thereof are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, and among them, methyl is most preferable. In the saturated alkyl (c), any carbons in the saturated alkyl may optionally be substituted by 1-3 halogens, and examples thereof are chloromethyl and trifluoromethyl. When R4 is xe2x80x94NR62, the group R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, and methyl are preferable.
Examples of xe2x80x94NR62 are amino, dimethylamino and diethylamino, and among them, dimethylamino is preferable. Consequently, examples of the group xe2x80x94SO2R4 are methylsulfonyl, ethylsulfonyl, chloromethylsulfonyl, trifluoromethylsulfonyl, sulfamoyl and N,N-dimethylsulfamoyl. Among them, preferable examples are methylsulfonyl and N,N-dimethylsulfamoyl and methylsulfonyl is most preferable.
Preferable examples of xe2x80x94NHZ in the group A are formylamino, acetylamino, propionylamino, hydroxyacetylamino, chloroacetylamino, carbamoylamino, N,N-dimethylcarbamoylamino, methylsulfonylamino and N,N-dimethylsulfamoylamino. Among them, formylamino, acetylamino, carbamoylamino and methylsulfonylamino are most preferable.
A group Q is defined as hydrogen, hydroxy or methoxy, and any substituents are most preferable.
Preferable scope of the compound of the present invention is a compound in the general formula (I), wherein n is integer of 2 or 3, R is n-butyl, isobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, 2-hydroxybutyl, 3-hydroxybutyl, 2-oxobutyl, 3-chlorobutyl, 4,4,4-trifluorobutyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, carbamoylmethyl or (N,N-dimethylcarbamoyl)methyl, Y is hydroxy or amino, A is hydrogen, hydroxy, methoxy, nitro, formylamino, acetylamino, propionylamino, hydroxyacetylamino, chloroacetylamino, carbamoylamino, N,N-dimethylcarbamoylamino, methylsulfonylamino, or N,N-dimethylsulfamoylamino, and Q is hydrogen, hydroxy or methoxy, or salt thereof.
More preferable scope of the compound of the present invention includes a compound in the general formula (I), wherein n is integer of 2 or 3, R is n-butyl, cyclohexylmethyl, carboxymethyl or carbamoylmethyl, Y is hydroxy or amino, A is hydrogen, formylamino, acetylamino, carbamoylamino or methylsulfonylamino, and Q is hydrogen, hydroxy or methoxy, or salt thereof.
The most preferable scope of the compound of the present invention includes a compound in the general formula (I), wherein n is 2, R is cyclohexylmethyl, Y is hydroxy or amino, A is hydrogen, formylamino, acetylamino, carbamoylamino or methylsulfonylamino, and Q is hydrogen, hydroxy or methoxy, or salt thereof.
Concrete examples of the compound of the present invention (I) can be mentioned as follows.
3-(2-butoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-isobutoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-pentyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclopentyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclopentylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-[2-(2-hydroxybutyloxy)-1,1xe2x80x2-biphenyl-5-yl]propionic acid;
3-[2-(2-oxobutyloxy)-1,1xe2x80x2-biphenyl-5-yl]propionic acid;
3-(2-carboxymethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-carbamoylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-butoxy-3-nitro-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(3-acetylamino-2-butoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-butoxy-3-methylsulfonylamino-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(3-acetylamino-2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-3-methylsulfonylamino-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-3-hydroxyacetylamino-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-[2-cyclohexylmethyloxy-3-(N,N-dimethylcarbamoylamino)-1,1xe2x80x2-biphenyl-5-yl]propionic acid;
3-[2-cyclohexylmethyloxy-3-(N,N-dimethylsulfamoylamino)-1,1xe2x80x2-biphenyl-5-yl]propionic acid;
3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-3-methoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-3-hydroxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-4xe2x80x2-hydroxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-4xe2x80x2-methoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-4,1xe2x80x2-biphenyl-5-yl)propionamide;
4-(2-butoxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-isobutoxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-[2-(-methylpropyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-(2-pentyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-[2-(1-methylbutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(2-methylbutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-(2-isopentyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-cyclopentyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-cyclohexyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-cyclopentylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl -5-yl)butyric acid;
4-[2-(4-hydroxybutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(3-hydroxybutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(2-hydroxybutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-(2-carboxymethyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-[2-(2-carboxyethyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(3-carboxypropyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-(2-carbamoylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-[2-(N,N-dimethylcarbamoylmethyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(N,N-diethylcarbamoylmethyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-(2-butoxy-3-nitro-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-butoxy-3-formylamino-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(3-acetylamino-2-butoxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-butoxy-3-methylsulfonylamino-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-butoxy-3-methoxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-butoxy-1,1xe2x80x2-biphenyl-5-yl)butyramide;
4-(2-carbamoylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)butyramide;
4-[2-(3-carbamoylpropyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyramide;
4-[2-(4-chlorobutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(3-chlorobutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(4-bromobutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid; and
4-[2-(4,4,4-trifluorobutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
Among them, compounds having optical isomer are as follows.
3-[2-(2-hydroxybutyloxy)-1,1xe2x80x2-biphenyl-5-yl]propionic acid;
4-[2-(1-methylpropyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(1-methylbutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(2-methylbutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(3-hydroxybutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid;
4-[2-(2-hydroxybutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid; and
4-[2-(3-chlorobutyloxy)-1,1xe2x80x2-biphenyl-5-yl]butyric acid.
These optical isomers and mixtures thereof are preferable examples of the compound (I).
The specifically preferable compounds (I) of the present invention can be listed as follows.
3-(2-butoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-carboxymethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid,
3-(2-carbamnoylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(3-acetylamino-2-butyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-butoxy-3-methylsulfonylamino-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(3-acetylamino-2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-3-methylsulfonylamino-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(3-carbamoylamino-2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-4xe2x80x2-hydroxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-4xe2x80x2-methoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid;
3-(2-cyclohexylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)propionamide;
4-(2-butoxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-cyclohexyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-carboxymethyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-carbamoylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-butoxy-3-formylamino-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(3-acetylamino-2-butoxy-1,1xe2x80x2-biphenyl-5-yl)butyric acid
4-(2-butoxy-3-methylsulfonylamino-1,1xe2x80x2-biphenyl-5-yl)butyric acid;
4-(2-butoxy-1,1xe2x80x2-biphenyl-5-yl)butyramide; and
4-(2-carbamnoylmethyloxy-1,1xe2x80x2-biphenyl-5-yl)butyramide.
Salt of the compound (I) is preferably pharmaceutically acceptable salt, and in case that Y is hydroxy; W is carboxy; or A or Q is phenolic hydroxy, it means salt of any one or more of these groups. One to four alkaline salts can be formed depending on numbers of acidic groups, and examples of salt are salt with inorganic base such as sodium and ammonium, or organic base such as triethylamine.
The compound (I) of the present invention can be produced, for example, by the following various methods.
[The Process for Production 1]
(Process a)
A Compound of the General Formula II, which is the compound (I) of the present invention, wherein Y is hydroxy; 
wherein n, R, A and Q have the same meaning hereinbefore, [hereinafter designates as simply xe2x80x9cthe compound (II)xe2x80x9d]can be produced by hydrolyzing a compound of the general formula (III) [hereinafter designates as simply xe2x80x9cthe compound (III)xe2x80x9d]
wherein Rxe2x80x2 is a straight or branched saturated alkyl of C4 or C5 (axe2x80x2), cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or xe2x80x94(CH2)mW, proviso that in the saturated alkyl (axe2x80x2), any carbons except for carbon constructing the ether bond may optionally be substituted by one of hydroxy or acetoxy; secondary carbon except for carbon constructing the ether bond may optionally be substituted by one of oxo; or any carbons except for carbon constructing the ether bond may optionally be substituted by 1-3 halogens; W is xe2x80x94CONR1R2 or alkyloxycarbonyl which can be converted to carboxy by hydrolysis, or nitrile; Yxe2x80x2 is lower alkoxy such as methoxy or ethoxy; Al is hydrogen, hydroxy, methoxy, nitro or xe2x80x94NHZxe2x80x2, in which Zxe2x80x2 is xe2x80x94COR3xe2x80x2 or xe2x80x94SO2R4,R3xe2x80x2 of which is hydrogen or saturated alkyl of C1-4 (bxe2x80x2) or xe2x80x94NR52; any carbons in the saturated alkyl (bxe2x80x2) may optionally be substituted by one of acetoxy or 1-3 halogens; Q1 is hydrogen, hydroxy, methoxy, acetoxy or benzoyloxy; and n, m, R1, R2, R4 and R5 have the same meanings hereinbefore, with base in a polar solvent, converting a group Yxe2x80x2 to hydroxy, and simultaneously converting, if those groups exist, acetoxy in the saturated alkyl (axe2x80x2) to hydroxy, alkyloxycarbonyl or nitrile in Wxe2x80x2 to carboxy, acetoxy in the saturated alkyl (bxe2x80x2) to hydroxy, or acetoxy or benzoyloxy in the group Q to hydroxy.
Examples of base used herein are alkaline metal salt such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide and potassium t-butoxide, and organic base such as triethylamine. Amount of use thereof is, generally, 1-20 molar excess in case of alkaline metal salt, preferably 1-10 molar excess, and equimolar to large excess in case of organic base.
Examples of polar solvent are water, methanol, ethanol, tetrahydrofuran and dioxane, and these can be used by mixing if necessary. Reaction temperature can be selected within suitable temperature from room temperature to reflux temperature of the solvent. Reaction time is usually 0.5-72 hours when alkaline metal salt is used, preferably 1-48 hours, and when organic base is used, it is usually from 5 hours to 14 days. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (II) reaches to maximum.
The thus obtained compound (II) can be isolated from the reaction mixture in the stage of free carboxyic acid, in case of the polar solvent being aqueous solvent, by distilling the solvent, neutralizing with inorganic acid such as hydrochloric acid, dissolving the residue with non-aqueous solvent, washing with weak acidic aqueous solution or water, and removing the solvent. In case that the polar solvent is non-aqueous solvent, the compound (II) can be isolated by neutralizing the reaction mixture, washing with water and removing the solvent.
In case that, after reaction, the compound (II) is solidified by forming salt with using base, salt of the compound (II) can be obtained by isolating it with conventional manner and being purified.
[The Process for Production 2]
(Process b-1)
A compound of the general formula (IV), which is the compound (I) of the present invention, wherein Y is amino and R is xe2x80x94(CH2)mCOOH; 
wherein Rxe2x80x3 is straight or branched saturated alkyl of C4 or C5 (a), cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or xe2x80x94(CH2)mCONR1R2, n, m, A, Q, R1, R2 and saturated alkyl (a) have the same meanings hereinbefore [hereinafter simply designates as xe2x80x9ccompound (IV)xe2x80x9d], can be produced by reacting, for example, the compound (II) hereinbefore with inorganic halogenide without presence of solvent or in an inert solvent to convert acid halogenide, which is then reacting with excess concentrated aqueous ammonia directly or dissolved in an inert solvent.
Examples of inorganic halogenide are thionyl chloride, phosphoryl chloride, phosphorus pentachloride and phosphorus trichloride, and among them, thionyl chloride is preferable. Amount of halogenide to be used is generally equivalent to large excess for the compound (II), preferably 1.5-5 molar excess. Examples of inert solvent are halogenated hydrocarbon such as dichloromethane, chloroform and 1,2-dichloroethane, ether such as tetrahydrofuran and dioxane and benzenes such as benzene, toluene, xylene and chlorobenzene. These solvents can be used alone or mixture thereof. Catalytic amount of N,N-dimethylformamide can optionally be added for stimulating the reaction. Reaction temperature can be selected generally at room temperature to reflux temperature of the solvent. Reaction time is usually 0.5-24 hours, preferably 1-6 hours.
Examples of inert solvent used in a reaction with ammonia are halogenated hydrocarbon such as dichloromethane, chloroform and 1,2-dichloroethane, ether such as tetrahydrofuran and dioxane and benzenes such as benzene, toluene, xylene and chlorobenzene. Reaction temperature can be selected generally from xe2x88x9210xc2x0 C. to room temperature. Reaction time is generally 0.5-24 hours, preferably 0.5-6 hours.
(Process b-2)
The compound (IV) can be produced according to a method described in New Experimental Chemistry Series (Japan Chemical Society Ed., Maruzen Publ. Co.), Vol. 14, page 1147, Ammonolysis, in which the compound (III) hereinbefore is reacted in an excess amount of concentrated aqueous ammonia in the presence of catalysis such as ammonium chloride, sodium methoxide or butyl lithium.
(Process b-3)
The compound (I), wherein Y is amino and R is xe2x80x94(CH2)mCOOH, i.e. a compound represented by the general formula (V) 
wherein n, m, A and Q have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (V)xe2x80x9d] can be synthesized by subjecting to amidation of the compound (III), wherein R is xe2x80x94(CH2)mCOOBn, i.e. a compound (VI) of the formula, 
wherein Bn is benzyl, and n, m, Yxe2x80x2, A and Q have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (VI)xe2x80x9d], according to a method of ammonolysis shown in the above process b-2, then the benzyl ester is hydrogenated using hydrogen source such as hydrogen gas in the presence of catalysis such as palladium carbon powder in an inert solvent such as methanol to convert carboxy.
The compound (III) [including the compound (VI)] used in the processes 1 and 2 for production of the compound (I) can be produced by, for example, the following methods 1-4 for synthesis of intermediates.
[Process for Production of Intermediate 1]
(Process c-1)
The compound (III), wherein A1 and Q1 are hydrogen, i.e. a compound (VII) of the general formula, 
wherein n, Rxe2x80x2 and Yxe2x80x2 have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (VII)xe2x80x9d], can be produced by reacting the compound of the formula (VIII), 
wherein n, and Yxe2x80x2 have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (VIII)xe2x80x9d], with the formula (IX),
Rxe2x80x2xe2x80x94Xxe2x80x83xe2x80x83(IX)
wherein X is halogen such as chlorine, bromine and iodine or sulfate such as p-toluenesulfonyloxy, methanesulfonyloxy and (2,4,6-trimethylphenyl) sulfonyloxy (mesitylenesulfonyloxy), and Rxe2x80x2 has the same meaning hereinbefore, (hereinafter simply designates as xe2x80x9calkylating agentxe2x80x9d), in an inert solvent in the presence of suitable base.
Examples of alkylating agent used herein are the straight or branched alkyl halide of C4 or C5 such as alkyl iodide, alkyl bromide, alkyl chloride or cyclohexylmethyl bromide, the haloalkane carboxylate such as bromoacetic acid ester and 4-bromobutyric acid ester, and the haloalkane carboxamide such as bromoacetamide and chloroacetic acid dimethylamide, in all of which carbon except for carbon binding with halogen is optionally substituted by an acetoxy, secondary carbon except for carbon binding with halogen is optionally substituted by an oxo, or carbon except for carbon binding with halogen is optionally substituted by 1-3 halogens, or the alkyl sulfate obtained by conventionally mesylated, tosylated or methylene sulfonylated straight or branched primary or secondary alcohol or cyclopentylmethyl alcohol, or the alkyl sulfate obtained by that the commercially available alkyl diol of C4 or C5 having primary and secondary hydroxy is conventionally methylenesulfonylated the primary alcohol, then the secondary alcohol is conventionally protected by acetyl. Amount of use thereof is generally equimolar to 40 molar excess, preferably equimolar to 10 molar excess, of the compound (VIII). Examples of inert solvent used in the reaction are alcohol such as methanol or ethanol, ether such as tetrahydrofuran or dioxane, benzens such as benzene, toluene or xylene, N,N-dimethylformamide, acetonitrile or acetone, and can be used if necessary with mixture thereof. Examples of base used herein are, for example, alkaline metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide and potassium t-butoxide, and tertiary organic amine such as pyridine, 4-dimethylamino pyridine, 1,8-diazabicyclo [5,4,0]-undecene, trimethylamine and triethylamine. Amount of use thereof is generally equimolar to 10 molar excess, preferably equimolar to 5 molar excess, of the compound (VIII). Reaction temperature can be selected within suitable temperature from room temperature to reflux temperature of the solvent, preferably at room temperature to 80xc2x0 C. Reaction time is usually 1 hour-6 days, preferably 2-48 hours. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (VII) reaches to maximum. In case of slow reaction, 0.1-1.5 molar excess of catalyst such as potassium iodide or copper powder can optionally be added.
(Process c-2)
The compound (VII) can be produced by the Mitsunobu reaction from the compound (VIII) according to the reference (O. Mitsunobu, Synthesis, page 1, 1981). Namely, it can be obtained by reacting the compound (VIII) in organic solvent in the presence of phosphine such as triphenylphosphine and tributylphosphine and azo compound such as diethyl azodicarboxyate, N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl azodicarboxamide, 1,1xe2x80x2-(azodicarbonyl) dipiperidine and N,N,Nxe2x80x2,Nxe2x80x2-tetraisopropyl carboxamide, with commercially available straight or branched primary or secondary alcohol of C4 or C5, cyclopentyl alcohol, cyclohexyl alcohol or cyclopentylmethyl alcohol. Examples of solvent are ether such as diethyl ether, tetrahydrofuran or dimethoxyethane, and benzens such as benzene, toluene or xylene, and can be used if necessary with mixture thereof. Amount of phosphins used is generally equimolar to 10 molar excess, preferably 1.5 to 5 molar excess, of the compound (VIII). Amount of azo compound used is generally equimolar to 10 molar excess, preferably 1.5 to 5 molar excess, of the compound (VIII). Reaction temperature can be selected within suitable temperature from xe2x88x9220xc2x0 C. to room temperature, preferably at 0xc2x0 C. to room temperature. Reaction time is usually 3 hours-3 days, preferably 6-24 hours. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (VII) reaches to maximum.
(Process c-3)
The compound (VII), wherein Rxe2x80x2 is 2-hydroxy alkyl of C4 or C5, can also be produced by reacting the compound (VIII) with the corresponding 1,2-epoxy alkane such as 1,2-epoxy butane and 1,2-epoxy pentane in the presence of base in an organic solvent. Amount of 1,2-epoxy alkane used is generally equimolar to large excess, preferably 3 to 10 molar excess, of the compound (VIII). Examples of base used herein are, for example, alkaline metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide and potassium t-butoxide, and tertiary organic amine such as pyridine, 4-dimethylamino pyridine, 1,8-diazabicyclo [5,4,0]-undecene, trimethylamine, triethylamine and diisopropylethylamine. Amount of use thereof is generally equimolar to large excess, preferably 3 to 20 molar excess, of the compound (VIII).
Since this reaction needs for long time, it is preferably proceeded in the autoclave. Examples of solvent used are alcohol such as methanol or ethanol, ether such as tetrahydrofuran or dioxane, benzens such as benzene, toluene or xylene, N,N-dimethylformamide, acetonitrile or acetone. Reaction temperature is generally at room temperature to 200xc2x0 C. Reaction time is generally for 1 hour to 7 days.
(Process c-4)
The compound (VII), wherein Rxe2x80x2 is xe2x80x94(CH2)2W, can be produced by reacting the compound (VI) with acrylic acid derivative such as acrylate, acrylamide or acrylonitrile and base, if required adding copper catalyst. Amount of acrylic acid derivative is generally 2 molar excess to large excess of the compound (VIII). Examples of base used in this reaction are alkaline metal such as metallic sodium, sodium methoxide and potassium t-butoxide, tertiary ammonium such as toriton B (trimethylbenzyl ammonium hydroxide), and tertiary organic amine such as trimethylamine, triethylamine and isopropyl ethylamine. Examples of copper catalyst are cupric hydroxide and copper acetate hydrate. Amount used thereof is generally 0.1xe2x80x94equimolar of the compound (VIII). Reaction can be proceeded generally in acrylic acid derivative as a solvent or in alcohol such as methanol and ethanol or benzenes such as benzene, toluene and xylene. Reaction time is usually 3-24 hours. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (VII) reaches to maximum.
(Process d)
The compound (VIII), wherein n is 2, can be produced by conventionally demethylating the known 3-(2-methoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid disclosed in the reference (R. R. Burtner et al. J. Am. Chem. Soc. 75: 2334, 1953) and conventionally esterifying the carboxyic acid. For example, 3-(2-methoxy-1,1xe2x80x2-biphenyl-5-yl)propionic acid can be obtained by reacting at about 180xc2x0 C. in pyridine-hydrochloric acid complex to convert methoxy to hydroxy, and reacting the thus obtained compound with thionyl chloride in alcohol such as methanol.
(Process d)
The compound (VIII), wherein n is 3, can be produced by demethylating and esterifying the compound of the formula (X), [hereinafter simply designates as xe2x80x9cthe compound (X)xe2x80x9d], 
wherein Yxe2x80x3 is hydroxy or lower alkoxy such as methoxy and ethoxy, according to the same method described in the process d for production of the intermediate 1.
(Process e)
The compound (X) can be produced by reducing a ketone carbonyl of the formula (XI), [hereinafter simply designates as xe2x80x9cthe compound (XI)xe2x80x9d], 
wherein Yxe2x80x3 has the same meaning hereinbefore, according to a method described in the reference (K. P. Mathai et al. J. Indian Chem. Soc. 42: 86, 1965).
The compound (X) can also be produced by hydrogenating the compound (XI) by using hydrogen source such as hydrogen gas, ammonium formate and hydrazine hydride in inert solvent in the presence of catalyst. Examples of inert solvent are alcohol such as methanol and ethanol, halogenated hydrocarbon such as dichloromethane and 1,2-dichloroethane, ether such as tetrahydrofuran and dioxane, and ethyl acetate, and these solvent can optionally be used in a mixture thereof. Trace amount of acid such as hydrochloric acid and acetic acid can be added for stimulating the reaction. Catalyst used herein is palladium carbon powder, platinum oxide, and the like.
(Process f)
The compound (XI), wherein Yxe2x80x3 is hydroxy, i.e. 3-(4-methoxy-3-phenylbenzoyl)propionic acid is a known compound in the reference (R. R. Burtner et al. J. Am. Chem. Soc. 75: 2334, 1953). The compound, wherein Yxe2x80x3 is lower alkoxy such as methoxy and ethoxy, can be produced by reacting the commercially available 2-methoxy biphenyl with 3-alkoxycarbonyl propionyl chloride in the presence of Lewis acid catalyst in Friedel-Crafts reaction. Amount of acid chloride is generally 1-10 molar excess, preferably 1.5-4 molar excess of the raw material. Examples of Lewis acid are aluminum chloride, tin chloride or titanium chloride. Amount of these materials is generally 1-10 molar excess, preferably 1-4 molar excess. Example of solvent used in the reaction is halogenized hydrocarbon such as dichloromethane and 1,2-dichloroethane, nitrobenzene and carbon disulfide. Reaction temperature is selected suitable temperature of generally at xe2x88x9210-100xc2x0 C., preferably 0xc2x0 C.xe2x80x94room temperature. Reaction time is usually 1-16 hours, preferably 2-8 hours. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (XI) reaches to maximum.
[Process for Production of Intermediate 2]
(Process d)
The compound (III), wherein any one of A1 and Q1 is hydrogen and n is 2, i.e. a compound (XII) of the general formula, 
wherein A2 and Q2 are hydrogen or hydroxy, and at least one of them is hydroxy, and Rxe2x80x2 and Yxe2x80x2 have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XII)xe2x80x9d], can be produced by the same process of demethylating and esterifying the compound of the formula (XIII), 
wherein A3 is hydrogen or methoxy, and Rxe2x80x2 and Y7 have the same meanings hereinbefore and at least one of them is other than hydrogen [hereinafter simply designates as xe2x80x9cthe compound (XIII)xe2x80x9d], as shown in the process for production of intermediate 1, process d.
(Process g)
The compound (XIII) can be produced by catalytic reaction of the compound (XIV) of the formula, 
wherein Q3 is hydrogen, methoxy or benzyloxy, Rxe2x80x2, Yxe2x80x3 and A3 have same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XIV)xe2x80x9d], as described in the chemical reference. For example, double bond in the compound (XIV) is hydrogenated by using hydrogen source such as hydrogen gas, ammonium formate and hydrazine hydride, in alcoholic solvent such as methanol or ethyl acetate alone or with mixture, in the presence of catalyst such as palladium carbon, and simultaneously converting benzyloxy of Q3 to hydroxy, if it exists.
(Process h)
The compound (XIV) can be produced, for example, according to a method described in New Experimental Chemistry Series (Japan Chemical Society Ed., Maruzen Publ. Co.), Vol. 14, page 238, Homer-Emmons reaction, from the compound (XV) of the formula (XV), 
wherein Rxe2x80x2, A3 and Q3 have same meanings hereinbefore and at least one of A3 and Q3 is other than hydrogen, [hereinafter simply designates as xe2x80x9cthe compound (XV)xe2x80x9d]. Namely, the compound (XV) is reacted with the commercially available dialkyl phosphono acetic acid ester in inert solvent, for example alcohol such as methanol and ethanol, or ether such as tetrahydroftiran and dimethoxy ethane, in the presence of sodium hydride or sodium alkoxide. Reaction temperature is generally at xe2x88x9210xc2x0 C.xe2x80x94reflux temperature of the solvent, preferably at 0xc2x0 C.xe2x80x94room temperature. Reaction time is generally at 1-16 hours, preferably at 2-8 hours. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (XIV) reaches to maximum.
(Process i)
The compound (XV) can be produced from the compound (XVI) of the formula, 
wherein Xxe2x80x2 is bromine or iodine, and Rxe2x80x2 and A3 have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XVI)xe2x80x9d] and the compound (XVII) of the formula, 
wherein Q3 has the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XVII)xe2x80x9d], according to the method described in Experimental Chemistry Series, 4th Ed. (Japan Chemical Society Ed., Maruzen Publ. Co.), Vol. 25, page 403, Suzuki reaction. Namely, the compound can be obtained by reacting the compound (XVI) with the compound (XVII) in solvent in the presence of catalyst prepared from phosphine such as triphenyl phosphine, tri(o-toryl)phosphine, 1,2-bis(diphenyl phosphino)ethane and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene and palladium complex such as palladium acetate and trisdibenzylidene acetone palladium (O), or tetrakis(triphenylphosphine)palladium (O) catalyst, and base such as potassium carbonate, sodium hydroxide or triethylamine. Examples of solvent are ether such as dioxane and dimethoxy ethane, benzens such as benzene, toluene and xylene, N,N-dimethylformamide and water, if necessary mixture thereof. Amount of catalyst used is generally 0.001xe2x80x94equimolar amount, preferably 0.01-0.10 molar excess of the compound (XVI). Amount of base used is generally 1-20 molar excess, preferably 1-5 molar excess of the compound (XVI). Amount of the compound (XVII) is generally 1-10 molar excess, preferably 1-5 molar excess of the compound (XVI). Reaction temperature is generally at xe2x88x9210xc2x0 C.xe2x80x94reflux temperature of the solvent, preferably at 0xc2x0 C.xe2x80x94room temperature. Reaction time is generally at 1-24 hours, preferably at 2-8 hours. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (XV) reaches to maximum. 4-benzyloxyphenyl boric acid in the compound (XVII) can be produced from the compound, which is produced by benzylating hydroxy in the commercially available 4-bormophenol, according to the reference (Y. Satoh et al. Synthesis, page 1146, 1994).
Process c)
The compound (XVI) can be produced by etherifying 3-bromo-4-hydroxybenzaldehyde, which is produced by conventional demethylation of the commercially available 3-bromo-4-methoxybenzaldehyde described in the Chemical references, or the commercially available 5-iodovanillin according to any methods shown in the prior process c in the production method of the intermediate 1.
[Process for Production of Intermediate 3]
(Process d)
The compound (III), wherein Axe2x80x2 or Qxe2x80x2 is hydroxy and n is 3, i.e. the compound (XVIII)of the formula, 
wherein Rxe2x80x2, Yxe2x80x2, A2 and Q2 have the same meanings hereinbefore, and at least either A2 or Q2 is hydroxy, [hereinafter simply designates as xe2x80x9cthe compound (XVIII)xe2x80x9d], can be produced by demethylating and esterifying the compound of the formula (XIX), 
wherein Rxe2x80x2, Yxe2x80x3, A3 and Q have the same meanings hereinbefore, and at least either A3 or Q is other than hydrogen, [hereinafter simply designates as xe2x80x9cthe compound (XIX)xe2x80x9d], according to the same method described in the process d for production of the intermediate 1.
(Process e)
The compound (XIX) can be produced from the compound (XX) of the formula, 
wherein Rxe2x80x2, Yxe2x80x3, A3 and Q3 have the same meanings hereinbefore, and at least either A3 or Q3 is other than hydrogen, [hereinafter simply designates as xe2x80x9cthe compound (XX)xe2x80x9d], according to the same method described in the process e for production of the intermediate 1.
(Process f)
The compound (XX) can be produced from the compound (XXI) of the formula, 
wherein Rxe2x80x2, A3 and Q3 have the same meanings hereinbefore, and at least either A3 or Q3 is other than hydrogen, [hereinafter simply designates as xe2x80x9cthe compound (XXI)xe2x80x9d], according to the same method described in the process f for production of the intermediate 1.
(Process c)
The compound (XXI) can be produced from the compound (XXII) of the formula, 
wherein A3 and Q3 have the same meanings hereinbefore, and at least either A3 or Q3 is other than hydrogen, [hereinafter simply designates as xe2x80x9cthe compound (XXII)xe2x80x9d], according to the same method described in the process c for production of the intermediate 1.
(Process j)
The compound (XXII) can be produced by conventional demethoxymethylation of the compound (XXIII) of the formula, 
wherein A3 and Q3 have the same meanings hereinbefore, and at least either A3 or Q3 is other than hydrogen, [hereinafter simply designates as xe2x80x9cthe compound (XXIII)xe2x80x9d].
For example, the compound can be obtained by treating with acid such as phosphoric acid in the water miscible solvent such as dioxane.
(Process k)
The compound (XXIII) can be produced from the compound (XXIV) of the formula, 
wherein A3 has the same meaning hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XXIV)xe2x80x9d], and the compound (XXV) of the formula, 
wherein Q3 and Xxe2x80x2 have the same meanings hereinbefore, according to the method described in Experimental Chemistry Series, 4th Ed. (Japan Chemical Society Ed., Maruzen Publ. Co.), Vol. 25, page 401, cross-coupling reaction. For example, after the compound (XXIV) is lithiated by alkyl lithium such as n-butyl lithium and t-butyl lithium, the compound, which is subjected to metal exchange with zinc chloride, is reacted with the compound (XXV) in the presence of palladium catalyst such as tetrakis(triphenylphosphine)(O).
The compound (XXIV) can be produced from the commercially available phenol or 2-methoxy phenol and methoxymethyl chloride by the method shown in the process 3, process c-1.
The compound (XXV), wherein Q3 is benzyloxy, can be produced by reacting hydroxy of the commercially available 4-bromophenol with benzyl halide. The other type of compound (XXV) can easily be obtained.
[Process for Production of Intermediate 4]
(Process 1-1)
The compound (III), wherein A1 is xe2x80x94NHZxe2x80x2, i.e. the compound of the formula (XXVI), 
wherein Q4 is hydrogen, methoxy, acetoxy or benzoyloxy, n, Rxe2x80x2, Yxe2x80x2 and Zxe2x80x2 have the same meanings hereinbefore, can be produced by condensing the compound of the formula (XXVII), 
wherein n, Rxe2x80x2, Yxe2x80x2 and Q4 have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XXVII)xe2x80x9d], in an inert solvent with acylating agent such as acid anhydride, acid halide, N,N-dialkylcarbamoyl chloride, alkylsulfonyl chloride or N,N-dialkylsulfamoyl chloride, if necessary in the presence of base. Examples of inert solvent used herein are halogenated hydrocarbon such as dichloromethane and chloroform, ether such as tetrahydrofuran, dioxane and diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide and acetonitrile. These can be used alone or admixture.
Examples of acylating agent, for example, acid anhydride are acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, pivalic anhydride and trifluoroacetic anhydride. Examples of acid halide are acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, isovaleryl chloride, pivaloyl chloride, chloroacetyl chloride, acetoxyacetyl chloride and methoxyacetyl chloride. Examples of N,N-dialkylcarbamoyl chloride are N,N-dimethylcarbamoyl chloride and N,N-diethylcarbamoyl chloride. Examples of sulfonic anhydride are trifluoromethanesulfonic anhydride, etc. Examples of alkylsulfonyl chloride are methylsulfonyl chloride and ethylsulfonyl chloride. Examples of N,N-dialkylsulfamoyl chloride are N,N-dimethylsulfamoyl chloride, etc. Amount of use thereof is 1-20 molar excess, preferably 1-10 molar excess of the compound (XXVII).
Examples of base used in the above reaction are alkaline metal such as sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide and sodium methylate, and organic amine such as pyridine, trimethylamine and triethylamine. Amount use thereof is generally 1-20 molar excess, preferably 1-10 molar excess of the compound (XXVII).
Reaction temperature is generally at xe2x88x9230-120xc2x0 C., preferably xe2x88x9220-50xc2x0 C. Reaction time is generally at 0.5-72 hours, preferably at 0.5-48 hours. The reaction process can be traced by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), consequently, the reaction can be terminated when the yield of the compound (XXVI) reaches to maximum.
The compound (XXVI) hereinabove, wherein Zxe2x80x2 is formyl, can be produced by replacing the acylating agent in the above reaction to a mixture of 99% formic acid and acetic anhydride.
(Process 1-2)
The compound (XXVI), wherein Zxe2x80x2 is carbamoyl, can be produced, for example, by reacting the compound (XXVII) with 1-5 molar excess of alkaline metal cyanate (such as NaOCN and KOCN) in a mixture of water and acetic acid. Reaction temperature is generally at room temperature xe2x88x92100xc2x0 C. The reaction time is 1-24 hours.
(Process m)
The compound (XXVII) can be produced by hydrogenating nitro group of the compound (XXVIII) of the formula, 
wherein n, Rxe2x80x2, Yxe2x80x2 and Q4 have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XXVIII)xe2x80x9d], with the conventional method, for example, in a solvent such as methanol, in the presence of catalyst such as palladium carbon powder or palladium oxide, at room temperature or heated temperature, or by reducing with hydrochloric acid in the presence of iron powder or tin (II) salt at room temperature to reflux temperature.
(Process n)
The compound (XXVIII) can be produced by nitrating the compound (XXIX) of the formula, 
wherein n, Rxe2x80x2, Yxe2x80x2 and Q4 have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XXIX)xe2x80x9d], according to the conventional method described in the chemical reference. For example, a mixture of 70-98% nitric acid and acetic anhydride solution was added to acetic anhydride solution of the compound (XXIX) and reacted at xe2x88x9220-5xc2x0 C.
(Process o)
The compound (XXIX) can be produced by acetylating or benzoylating the compound (XXX) of the formula, 
wherein n, Rxe2x80x2, Yxe2x80x2 and Q have the same meanings hereinbefore, [hereinafter simply designates as xe2x80x9cthe compound (XXX)xe2x80x9d], according to the conventional method. For example, the compound (XXX) is reacted with acetyl chloride or benzoyl chloride at 0xc2x0 C.xe2x80x94room temperature.
The compound (I) of the present invention having assymetric carbon in the substituent R can be isolated as optical isomer of the objective product or its precursor by conventional method. Such the methods include a method of high performance liquid chromatography (HPLC) using optically active column (process p) and a method, in which the compound is condensing with optically active compound, separating the produced diastereoisomer and decomposing the same again. In case that the precursor is isolated to form optical isomer, thereafter the aforementioned process is performed, then the optical isomer of the objective compound (I) can be produced.
The compound (I) of the present invention having acidic functional group such as carboxy and phenolic hydroxy can be converted to pharmaceutically acceptable salt (such as inorganic salt with sodium or ammonium, or organic salt with triethylamine) by conventional method.
In order to obtain inorganic salt, for example, the objective compound (I) is preferably dissolved in aqueous solution containing at least equimolar amount of hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. In the reaction, water miscible inert organic solvent such as methanol, ethanol, acetone and dioxane can be mixed. For example, when sodium hydroxide, sodium carbonate or sodium bicarbonate is used, solution of sodium salt can be obtained.
In case that solid salt is required, the solution is evaporated, or slightly polar solvent of water miscible organic solvent such as butanol or ethylmethyl ketone is added to obtain solid salt.
The compounds described in the specification of the present invention can be purified by known methods such as recrystallization or chromatography (column chromatography, flush column chromatography, TLC and HPLC).
The compound (I) of the present invention and pharmaceutically acceptable salt thereof has no effect for production of immunoglobulin G (IgG), which is thought to be important for biological reaction such as prevention of infection, has selective suppressive action against IgE antibody production, and shows no death when administered orally 300 mg/kg in rats. Consequently, it is safe compound for pharmaceuticals and is useful as an active ingredient of the pharmaceuticals. Preferable use of the compound (I) of the present invention as pharmaceuticals includes suppressive agent for IgE antibody production and drug for treatment and/or prevention of allergic diseases caused by IgE antibody production such as bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis and anaphylaxis.
In order to use the compound (I) of the present invention or pharmaceutically acceptable salt thereof as the above pharmaceuticals, effective amount of the compound (I) or pharmaceutically acceptable salt thereof can be used directly or mixed with pharmaceutically acceptable carrier to prepare pharmaceutical composition. Such the carrier can be a suspending agent such as carboxymethyl cellulose or purified water and physiological saline, and other known carriers.
Examples of the pharmaceutical form for preparing formulation of the above pharmaceutical composition are tablet, powder, granule, syrup, suspension, capsule and injection. Various carriers are used for these formulations. For example, carriers for oral formulation include excipient, binder, lubricant, fluid promoter and coloring agent.
Parenteral formulation of the compound of the present invention such as injection can be prepared generally by mixing, for example, with distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, propylene glycol and polyethylene glycol. In addition, in necessary, bactericide, antiseptics, stabilizer, tonicity agent and soothing agent can be added.
In case of administration of the compound of the present to humans, it can be administered orally in the form of tablet, powder, granule, suppository, suspension and capsule. Parenteral administration can be performed in the form of injection including drip infusion, cream or spray. Amount of administration depends on diseases, administration form, age, body weight, and symptoms, but in general 3-1000 mg, 1-3 times per day per adult are administered. Term for administration is generally from several days to 2 months, but the daily dose and dosage term can be changed depending of symptom of patients.